Epinastine, chemically known as 3-amino-9,13b-dihydro-1H-dibenz-[c,-f]imidazol[1,5-a]azepine, and its acid addition salts are disclosed in German Patent application P 30 08 944.2 which forms the basis for EP 0035749. Methods for the preparation of epinastine are described in EP 0496306 or WO 01/40229. Epinastine is most often used for its antihistaminic effects.
Epinastine hydrochloride (ELASTAT®) has been approved as an eye drop in U.S. for treating allergic conjunctivitis. Epinastine hydrochloride has been approved as an oral tablet in Japan and some South American countries for treating allergic rhinitis. However, especially for children and elderly people, tablets are not always easy to take. It is found that aqueous formulations of epinastine-hydrochloride result in bad taste, reported as bitterness or bitter aftertaste.
The bitter taste of epinastine is strong. Many attempts have been made to reduce the bitter taste of epinastine. Prior art methods all involve using taste masking agents, particularly sweetening agents to mask the bitter taste of epinastine.
US2003/0104017 discloses a pharmaceutical formulation comprising epinastine or an acid addition salt thereof, and at least two kinds of sweeteners or flavoring agents, wherein one of the at least two kinds of sweeteners or flavoring agents masks the quick-acting bitterness of epinastine or its salt and the other one masks the long-acting bitterness of epinastine or its salt.
WO2004/075900 discloses pharmaceutical powder formulation comprising epinastine, sodium lauryl sulfate, sweetening agents and/or flavoring agents.
US2003/0050303 broadly discloses a method for inhibiting the influx of neutrophils and eosinophils into the tissue of the ocular conjunctiva or the nasal mucous membrane in a host, the method comprising topically administering to a host in need of such treatment an aqueous solution comprising epinastine, optionally in the form of its racemate, its enantiomers, or its pharmacologically acceptable acid addition salts thereof, in a concentration of 0.005 to 0.5 mg/ml of solution. The reference did not mention the problem of bitter taste of epinastine nor provided a solution to it.
Azelastine hydrochloride is another antihistamine with an even worse taste (extremely bitter and pungent taste) than epinastine at a much lower concentration. ASTELIN® (0.1% azelastine hydrochloride) nasal spray was approved for treating allergic rhinitis in the United States. When ASTELIN® was administered to subjects at 137 μL per spray, two sprays per nostril, twice daily, 19.7% of subjects reported adverse events of bitter taste (see product package insert of ASTELIN® nasal spray).
US2006/0110331 discloses a method for reducing the bitter taste of azalastine by delivering a composition comprising azelastine, hypromellose as a viscosity modifier and at least one taste-masking agent such as sucralose.
Currently, there is not an effective method for treating allergic rhinitis with an aqueous intranasal spray formulation which does not include a taste masking agent such as a sweetening agent. There is a need for an improved aqueous nasal spray formulation for treating allergic rhinitis; such aqueous nasal spray formulation is not only effective to treat allergic rhinitis but also has an acceptable taste profile following repeated dosing.